[HSF] Heparin Induced Thrombocytopenia and CABG
Claudia Teles
cvteles at gmail.com
Tue Oct 16 10:44:33 EDT 2007
Here in Brazil, the only drug available for that, and it's very difficult to
get is Argatroban. It is not reversible easily too.
But some time ago, similar problem was posted in this list, and someone sent
to the list a wonderful prostacyclin protocol. Iloprost is a good
alternative, but, I shall warn that it might represent a second challenge to
the patient's immune system, and this patient might go on producing anti PF4
antibodies for a longer time, because of another prolongued exposition to
heparin.
Were I in your shoes, I would try this.
Claudia Teles
British Journal of Anaesthesia, 2003, Vol. 90, No. 5 *676-685*
(c) 2003 The Board of Management and Trustees of the British Journal of
Anaesthesia <http://bja.oxfordjournals.org/misc/terms.shtml>
------------------------------
Review Article *HIT*/*HIT*T and alternative anticoagulation: current
concepts *E. Pravinkumar and N. R. Webster *
*Academic Unit of Anaesthesia and Intensive Care, Institute of Medical
Sciences, Foresterhill, Aberdeen AB25 2ZD, UK *
*Corresponding author. Email: e.pravinkumar at abdn.ac.uk*
Accepted *for* publication: July 25, 2002
*Abstract*
*Br J Anaesth* 2003; *90*: 676–85
*Keywords*: blood, coagulation; blood, anticoagulants, heparin
Heparin is a widely used anticoagulant *for* the treatment and prevention of
thromboembolic disorders in medical and surgical patients. Its importance as
an anticoagulant has been well established by its effectiveness, rapid onset
of action, ease of laboratory monitoring and
cost.18<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C18>Heparin
is a member of the heterogeneous family
of glycosaminoglycans, which range in size from 3000 to 30 000 Da.
The non-branching, negatively charged chain structure of heparin consists of
repeating disaccharide units. Heparin is an anticoagulant released by mast
cells and basophils in the process of clot *for*mation, as well as a drug
that is administered to the same effect. Standard unfractioned heparin is
usually derived from porcine intestinal mucosa or bovine
lung.53<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C53>
Heparin plays many roles in human physiology, such as: (i) binding to
antithrombin III and increasing the efficacy of antithrombin III as an
inhibitor of the activation of thrombin and certain clotting factors; (ii)
inhibiting platelet *for*mation; (iii) increasing the permeability of vessel
walls; (iv) inhibiting the proliferation of vascular smooth muscle cells;
and (v) playing a role in the regulation of angiogenesis.
In clinical use heparin has numerous activities, but the most important is
its anticoagulant property (Table
1<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063TB1>).
It is also used as a thrombolytic, a fat-clearing anti-atherosclerotic and
as a potentially effective anti-inflammatory agent. Heparin inhibits
reactions that lead to clotting of blood and *for*mation of fibrin clots
both *in vitro* and *in vivo*. It acts at multiple sites in the normal
coagulation system. It binds to antithrombin III (heparin cofactor), causing
a con*for*mational change in the structure of antithrombin III. This con*for
*mational change converts antithrombin III from a slow- to a fast-acting
inhibitor of thrombin activation. The complex has a further inhibitory
effect on other clotting factors, such as factors IX, X, XI and XII and
kallikrein, and on the conversion of prothrombin to
thrombin.50<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C50>
62 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C62> Once
active thrombosis has developed, larger amounts of heparin can inhibit
further coagulation by inactivating thrombin and preventing the conversion
of fibrinogen to fibrin. Heparin also prevents the *for*mation of a stable
fibrin clot by inhibiting the activation of the fibrin-stabilizing factor.
*View this table:*
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*Table 1* Clinical uses of heparin
*Thrombocytopenia and heparin*
Thrombocytopenia can result from conditions that lead to increased platelet
destruction or decreased platelet production (Table
2<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063TB2>
).8 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C8>
40<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C40>
57 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C57>Heparin
can cause thrombocytopenia via immune
and non-immune mediated
mechanisms.41<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C41>There
are two types of
heparin-induced thrombocytopenia that can result from heparin administration:
type I, non-immune-mediated; and type II,
immune-mediated.23<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C23>
67 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C67>
68<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C68>
In
the interest of standardization, the term 'non-immune heparin-associated
thrombocytopenia' is recommended *for* type I, a benign condition in which
no heparin-dependent antibodies are present. The term 'heparin-induced
thrombocytopenia' (*HIT*) is recommended *for* thrombocytopenia in which
pathogenic heparin-dependent antibodies are detectable. This term is the most
widely accepted designation *for* *HIT* type
II.67<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C67>
*View this table:*
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*Table 2* Causes of thrombocytopenia
*Non-immune-mediated thrombocytopenia*, also known as
heparin-associated thrombocytopenia
(HAT) and heparin-induced thrombocytopenia type I (*HIT* type I), denotes
the absence of heparin-dependent antibodies. It is probably caused by direct
non-immune platelet activation by heparin. Type I *HIT* is usually
associated with larger doses of heparin in contrast to *HIT* type II, which
can occur with variable doses. *HIT* type I occurs earlier in the treatment
course, within a period of 4 days, in 30% of patients receiving heparin. The
platelet abnormality is usually mild and reversible even with the
continuation of the heparin (Table
3<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063TB3>).
The condition is self-limiting and there are no major complications
associated with it. Heparin should be continued despite the low platelet
count.23 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C23>
67 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C67> The
clinical importance of the asymptomatic, self-limiting disease *HIT* type I
lies in the necessity of differentiating it from the more serious *HIT* type
II.
*View this table:*
[in this window]<http://bja.oxfordjournals.org/cgi/content/full/90/5/676/AEG063TB3>
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*Table 3* Heparin-induced thrombocytopenia68
*Immune-mediated HIT type II* exists in three separate diagnosable *for*ms:
(i) latent: antibodies without thrombocytopenia;
(ii) *HIT*: antibodies with thrombocytopenia; and
(iii) *HIT*T: antibodies with thrombocytopenia and thrombosis.
*HIT/HITT* (heparin-induced thrombocytopenia and heparin-induced
thrombocytopenia
with thrombosis syndrome) is an immune-mediated adverse reaction to heparin
that is often underdiagnosed and can result in venous and arterial
thrombosis.6<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C6>
56 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C56>
67<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C67>
69 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C69>–73<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C73>
79 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C79> The
alternative name of *HIT*T, w*hit*e clot syndrome, refers to the gross
pathology of the clots. The platelet–platelet adhesion without erythrocyte
involvement gives a classic appearance of a w*hit*e clot. Patients with *HIT
*T may suffer from venous thrombosis, most often deep venous thrombosis
(DVT), which can be extensive and complicated by pulmonary embolism. Venous
limb gangrene has been reported to occur with warfarin treatment of *HIT*
-associated DVT, and is characterized by a high international normalized ratio
(INR), resulting from severe reduction in protein C caused by warfarin.
Adrenal vein thrombosis and cerebral sinus thrombosis are other unusual
venous thromboses that complicate *HIT*. Arterial thromboses associated with
*HIT*T may result in ischaemic limb damage that often requires amputation.
Myocardial infarction, ischaemic stroke and end-organ thromboses, such as
mesenteric, renal, brachial, splenic and hepatic arterial thromboses, can also
occur (Table 4<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063TB4>
).10 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C10>
23<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C23>
47 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C47>
74<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C74>
*HIT* develops in 3% of patients treated with unfractioned heparin
*for*more than
4 days.72<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C72>Without
treatment, mortality in
*HIT* patients with new thromboembolic complications is about 20–30%, with
equal morbidity caused by arterial and venous
thrombosis.11<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C11>
20 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C20>
75<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C75>
The
risk of venous thromboembolism from *HIT* is greater in high-risk surgical
patients than in medical patients. Also, 40–50% of *HIT* patients will have
a thrombotic event when heparin is
discontinued.25<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C25>
65 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C65>
74<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C74>
76 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C76>
*View this table:*
[in this window]<http://bja.oxfordjournals.org/cgi/content/full/90/5/676/AEG063TB4>
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*Table 4* Venous and arterial thromboses associated with heparin-induced
thrombocytopenia and thrombosis syndrome (*HIT*T)
*Mechanism of heparin–PF4–IgG complex*
Most patients with *HIT* produce immunoglobulin G (IgG) antibodies, commonly
IgG1 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C1>
4<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C4>
17 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C17>
55<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C55>against
macromolecular complexes
of platelet factor 4 (PF4) and heparin
(H–PF4).2<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C2>
11 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C11>
26<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C26>
37 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C37>
41<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C41>
63 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C63>
64<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C64>
The
high binding affinity between heparin and PF4 is probably attributable to a
high concentration of C-terminus lysine residues that interact strongly with
the highly negatively charged heparin molecule. Neither heparin nor PF4 is
normally antigenic, but the *for*mation of an H–PF4 complex induces a con*
for*mational change in both molecules. Upon binding to the heparin
molecule, PF4
exposes several antigenic epitopes, which trigger the immune reaction and
the production of immunoglobulin
G.45<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C45>
60 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C60>
82<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C82>
These
antibodies activate platelets through their FcRIIA receptors, causing
platelet destruction and release of prothrombotic platelet-derived
microparticles.12<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C12>Microparticles
in turn promote thrombin generation and
contribute to a hypercoagulable
state77<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C77>(Fig.
1 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063F1>). PF4,
a small peptide stored within the alpha granules of platelets, binds to
heparin and is released into the blood during treatment with
it.3<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C3>
*In vitro*, IgG–PF4–heparin complexes can activate
platelets.11<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C11>
38 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C38>
49<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C49>
64 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C64>Increased
propensity to
thrombosis in *HIT* is there*for*e probably mediated by thrombin generated
as a result of *in vivo* platelet
activation,13<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C13>
77 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C77> from
interaction between heparin–PF4–IgG immune complexes with Fc receptors on
platelets.38<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C38>A
minimum of 12–14 saccharides
is required to *for*m the antigenic complex with PF4. Heparin molecules with
a molecular weight >4000 Da have the potential to cause *HIT*. Hence
*HIT*is less common with low molecular weight
heparin (LMWH) than with unfractioned
heparin.21<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C21>
72 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C72> No
specific laboratory or clinical characteristics can predict which patients
will have isolated thrombocytopenia or have thrombocytopenia with thrombotic
complications.
<http://bja.oxfordjournals.org/cgi/content/full/90/5/676/AEG063F1>
*View larger version* (14K):
[in this window]<http://bja.oxfordjournals.org/cgi/content/full/90/5/676/AEG063F1>
[in a new window]<http://bja.oxfordjournals.org/cgi/content-nw/full/90/5/676/AEG063F1>
*Fig 1* Mechanism of action of heparin–PF4–IgG complex and the vicious
circle that leads to thrombus *for*mation and platelet destruction.
IgG=immunoglobulin G; PF4=platelet factor 4; GP=glycoprotein.
*Diagnosis of HIT*
Manifestations of *HIT* include an otherwise unexplained decrease in
platelet count and skin lesions at heparin injection sites, accompanied by *
HIT* antibody *for*mation. The platelet count during *HIT* can be variable,
but only rarely decreases to <20 000x109 litre–1. The median platelet count
nadir in several studies is [image: ~]50 000x109 litre –1. *HIT* should also
be suspected if the platelet count decreases by 30–50% after 5 days of
heparin treatment (Table
3<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063TB3>
).68 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C68>
78<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C78>The
occurrence of thromboembolic complications during
heparin therapy is another strong marker of
*HIT*.11<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C11>
23 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C23>
Regardless
of the degree of thrombocytopenia, the predominant clinical feature is
thrombosis and not bleeding. The decrease in platelet count almost always
occurs between days 5 and 15 after the introduction of
heparin,72<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C72>but
can develop earlier in
patients exposed to heparin during the previous 3
months.41<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C41>
Case
reports have shown thrombocytopenia developing within 10.5 h in patients
exposed to heparin in the last 100 days. Thus, a patient with a rapid
decrease in platelets soon after commencing heparin therapy, who has not
been exposed to heparin previously, probably has another aetiology *for* the
thrombocytopenia. During recovery from thrombocytopenia, heparin- dependent
antibodies in the serum decrease to undetectable levels by 50–85
days.78<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C78>Those
with undetectable antibody but a previous proven diagnosis
of *HIT* type II may take as long as 5 days to produce IgG antibodies and
thrombocytopenia.
*Laboratory diagnosis*
There are two main classes of assays *for* laboratory diagnosis of
*HIT*. *Activation
(functional) assays* include the platelet aggregation assay and the
serotonin release assay. The platelet aggregation assay involves the use of
washed platelets rather than platelet-rich plasma derived from normal
donors. This increases the reliability of activation
assays,27<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C27>
28 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C28>which
are per
*for*med in the laboratory with a specificity >90%. The disadvantages are
low sensitivity (35%) and the fact that assay reactivity varies between
donor platelets.11<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C11>
20 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C20> The
serotonin release assay measures the release of serotonin from platelet
aggregates. It relies on the aggregation of the platelets from the patient in
the presence of heparin. This assay has high sensitivity and specificity and
has been validated by blinded assessment of clinical
trials.58<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C58>The
disadvantages are that the assay is technically
demanding and involves the use of radioactive
materials.27<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C27>
28 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C28> Of
the various activation assays available, those that use washed platelets and
platelet serotonin release or heparin-induced platelet activation (HIPA) are
the most accurate.19<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C19>
31 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C31>
58<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C58>
70 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C70>
The other class of assay is the *antigen assay*. The heparin–PF4 enzyme-linked
immunosorbent assay (ELISA) relies on the specificity of *HIT* IgG
antibodies *for* the heparin–PF4 complex. This assay is 10 times more
sensitive than the serotonin release assay *for* detecting heparin-induced
antibodies. However, the heparin–PF4 ELISA is expensive and time-consuming.
The assay also responds to clinically insignificant antibodies more often
than activation assays, and hence has a lower
specificity.20<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C20>
64 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C64>
Most of the available laboratory tests *for* the diagnosis of *HIT* are
expensive, time-consuming, frequently contradictory to the clinical
presentation, and vary in sensitivity and specificity. Testing a patient
with a history of *HIT* be*for*e expected heparin re-exposure should there*
for*e be done with more than one sensitive test. Hence, the diagnosis of *
HIT* remains clinical. It should be suspected in patients who develop
thrombocytopenia with or without associated arterial or venous thrombosis
while on heparin.15<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C15>
*Prevention of HIT*
Currently there are no tests available to predict which patients are at high
risk of developing *HIT*. There*for*e, whenever heparin is clinically
indicated, it is necessary to assess the risk– benefit profile in all
patients. The following points should be considered in the prevention of *
HIT*:
(i) history of previous sensitization to heparin—requires initiation of
alternative anticoagulant therapy;
(ii) limit heparin duration to less than 5 days whenever possible;
(iii) early use of warfarin in patients requiring long-term anticoagulation,
except when *HIT* is diagnosed;
(iv) initiating warfarin at the start of heparin treatment in patients who
require long-term anticoagulation;
(v) use of LMWH—a prospective study shows LMWH is less likely to cause *HIT*and
*HIT*–IgG antibodies;72
(vi) avoid unnecessary heparin flushes;
(vii) use of porcine heparin (frequency of *HIT*, 1.3–8%) rather than bovine
heparin (frequency of *HIT*, 1.9–30.8%);11 68
(viii) regular monitoring of platelet count.
*Management of HIT*
After the clinical diagnosis or suspicion of *HIT*, heparin should be
discontinued promptly. The platelet count should be monitored carefully and
warfarin should not be used alone in patients with acute
*HIT*.67<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C67>Management
of the patient with
*HIT* is aimed at prevention of the thromboembolic complications seen in
50–70% of patients. The mortality associated with isolated
thrombocytopenia without
thrombosis is 21%. There*for*e, the principle of managing *HIT* is the
discontinuation of all *for*ms of heparin exposure and the institution of an
alternative anticoagulant.43<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C43>
74 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C74> The
diagnosis should be confirmed as soon as practicable, but treatment should
not be delayed *for* this reason. In the absence of thrombosis, cessation of
heparin has been the traditional mode of
therapy,65<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C65>but
several studies have shown that stopping heparin
may be inadequate because of the high risk of overt thrombosis (50%) in the
week after its interruption.9<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C9>
24 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C24>
29<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C29>
65 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C65>
74<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C74>
*Warfarin in HIT*
Warfarin should not be used alone to treat acute *HIT* complicated by DVT
because of the paradoxical risk of developing venous limb gangrene, which
causes more than half the limb loss attributable to *HIT* at one
centre.75<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C75>Rapid
loading with warfarin can cause depletion
of the anticoagulant vitamin K-dependent protein C faster than it depletes
procoagulant vitamin K-dependent
proteins.32<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C32>
57 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C57>
75<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C75>
77 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C77>. Higher
warfarin doses cause a rapid increase in the INR, but this is entirely a
result of earlier reduction of factor VII rather than a reduction in factor
II, a coagulable protein with a longer half-life. Initiating warfarin
therapy with a relatively high loading dose *for* rapid anticoagulation,
which is a common practice, may prove dangerous, particularly in
*HIT*.46<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C46>
75 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C75>
Although
other thrombin inhibitors have been introduced *for* continuing
anticoagulation in the place of heparin, warfarin still remains an option *
for* patients with *HIT* who require anticoagulation. Studies have shown
that aiming *for* modest levels of the INR with warfarin and a smaller
loading dose prevents the development of a potential hypercoagulable state
caused by a precipitous decrease in the concentration of protein
C.32<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C32>
66 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C66>
It is there*for*e important to start treatment in all patients with
*HIT*who remain at risk of thrombosis, including postoperative
patients
and those with sepsis. Thrombin inhibitors (lepirudin or argatroban) should
be used in these patients until the platelet count has recovered. Treatment
with thrombin inhibitors should also be considered *for* patients with acute
*HIT* without thrombosis (isolated *HIT*), because there is a high risk of
subsequent clinically evident thrombosis. Warfarin given to patients
adequately anticoagulated with lepirudin appears safe in acute *HIT*, but it
is prudent to delay starting warfarin until the platelet count has risen above
100x109 litre–1.33<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C33>
*Low molecular weight heparin and HIT*
Low molecular weight heparin does not bind strongly to plasma proteins and
endothelial cells; its bioavailability is much greater than with
unfractionated heparin and there is also a more predictable dose response.
However, low molecular weight heparins have a high *in
vitro*cross-reactivity rate with heparin-dependent antibodies,
reaching 100% in some very sensitive assays. Low molecular weight heparins
can cause *HIT*,72<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C72>and
when used in its
treatment there is a significant risk of recurrent or progressive
thrombocytopenia
with or without thrombosis. Because of these drawbacks, and as there are
other effective drugs available, low molecular weight heparins are not
recommended *for* the management of patients with
*HIT*.67<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C67>
*Danaparoid in HIT*
Danaparoid sodium (Orgaran(r)) does not contain heparin and is a low molecular
weight heparinoid*.* It is a mix of dermatan sulphate, glycosaminoglycans
and chondroitin sulphate. The use of danaparoid is associated with a
favourable outcome in 90% of patients with
*HIT*.11<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C11>The
main activity of danaparoid is against factor
Xa, with the anti-Xa:anti-IIa ratio of 22:1 resulting in inhibition of
fibrin *for*mation. The potential disadvantage is the prolonged half-life of
anti-factor Xa activity (around 25 h). This is disadvantageous
*for*patients who are at risk
of bleeding and who might need a surgical procedure. There is a 10–20%
cross-reactivity rate with *HIT* antibodies *in vitro*, although it is less
common *in vivo*.30<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C30>
78 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C78>Danaparoid
does
not interfere with INR measurements, and there*for*e allows concurrent and
easy monitoring of warfarin anticoagulation.
*Ancrod in HIT*
Ancrod, a fibrin inhibitor derived from the Malayan pit viper venom, is
another treatment option *for* *HIT*. Ancrod has not been widely used and
there is only one small study on 11
patients.16<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C16>
Being
a *for*eign protein, Ancrod induces resistance with prolonged use. There has
also been increased thrombin generation and warfarin-induced limb gangrene
in patients treated with it.
*Prostacyclin analogues in HIT*
*Prostacyclin* is a natural vasodilator and inhibitor of platelet aggregation.
Iloprost has been shown to be effective in suppressing *HIT*-induced
platelet aggregation and in preventing thrombotic complications. *
Prostacyclin* analogues have a short half-life of 15–30 min and have been
preferred in cardiac and vascular surgery *for* anticoagulant coverage in
patients with *HIT*. They are also used in intensive care units
*for*anticoagulation during
renal replacement therapy. The main side-effects are hypotension and
bradycardia.11<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C11>
23 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C23>
*Thrombin inhibitors in HIT*
Thrombin plays a central role in *HIT*-related thromboembolic complications
(Fig. 2 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063F2>).
Thrombin generation is enhanced in *HIT* by the concomitant activation of
platelets,13<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C13>the
generation of
platelet microparticles and the alteration of endothelial
cells.80<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C80>Thrombin
inhibitors such as lepirudin and argatroban have
found a greater role in the management of
*HIT*/*HIT*T.39<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C39>
<http://bja.oxfordjournals.org/cgi/content/full/90/5/676/AEG063F2>
*View larger version* (21K):
[in this window]<http://bja.oxfordjournals.org/cgi/content/full/90/5/676/AEG063F2>
[in a new window]<http://bja.oxfordjournals.org/cgi/content-nw/full/90/5/676/AEG063F2>
*Fig 2* Actions of thrombin. NO=nitric oxide; PgI2=prostaglandin I2;
t-PA=tissue plasminogen activator. Adapted with permission from Fuster and
Verstraete.22
Thrombin inhibitors currently available *for* the management of *HIT* and *
HIT*T are:
(i) lepirudin (Refludan(r));
(ii) argatroban (Argatroban(r), Novastan(r));
(iii) hirulog and bivalirudin (Angiomax(r)) and
(iv) desirudin (ReVase(r)).
Lepirudin is currently licensed *for* the treatment of *HIT*/*HIT*T in the
UK, the USA and Europe. Argatroban has recently been approved *for* use in
the prophylaxis and treatment of thrombosis in *HIT* in the USA and Canada.
Bivalirudin and desirudin are currently not licensed *for* use in *HIT*/*HIT
*T, although their use in the treatment of this condition has been reported.
*Hirudin* is a direct inhibitor of thrombin and acts independently of
cofactors such as
antithrombin.52<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C52>Unlike
heparin, hirudin is
not inactivated by PF4 and may be more effective in the presence of
platelet-rich thrombi.59<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C59>Hirudin
can also inhibit thrombin bound
to fibrin or fibrin degradation
products.80<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C80>
81 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C81>
*Lepirudin* (Refludan(r)) is a recombinant hirudin derived from yeast cells
and is a highly specific direct and irreversible inhibitor of thrombin. One
molecule of lepirudin binds with one molecule of thrombin. The half-life *
for* distribution and elimination is 10 min and 1.3 h respectively.
Lepirudin is almost exclusively excreted in the kidneys and hence
systemic clearance
of lepirudin is dependent on the glomerular filtration rate. It should there
*for*e be used cautiously in patients with chronic renal failure and should
be avoided in patients with acute renal failure (Table
5<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063TB5>).
There is an increased risk of bleeding with other anticoagulants,
thrombolytics and antiplatelet drugs. The usual adult dose is 0.4 mg kg–1 as a
bolus over 15–20 s, followed by 0.15 mg kg–1 h–1 initially; adjustments are
then made on the basis of the activated partial thromboplastin time (aPTT)
(Table 5 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063TB5>).
However, the dose should not exceed an infusion rate of 0.21 mg kg–1
h–1 without
checking *for* coagulation abnormalities. In haemodialysis patients and
patients with acute renal failure with creatinine clearance <15 ml
min–1(normally 120 ml min
–1) or serum creatinine >528 µmol litre–1, the drug should be avoided. The
infusion rate should be adjusted in patients with renal impairment
(Table 6<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063TB6>
).
*View this table:*
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*Table 5* Comparison between lepirudin and argatroban7
*View this table:*
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*Table 6* Dosing adjustment *for* lepirudin7
*Ecarin clotting time* (ECT) is a suitable assay *for* bedside
real-time monitoring
of lepirudin anticoagulation. Ecarin is a metalloproteinase from snake venom
(*Echis carinatum*) that activates prothrombin to meizothrombin. Hirudin *
for*ms a 1:1 complex with meizothrombin, thus preventing the conversion of
fibrinogen to fibrin and the *for*mation of thrombin. There*for*e, the
clotting time is prolonged with increasing amounts of hirudin. The precision
of the ECT assay is directly related to the prothrombin and fibrinogen
concentration,
but does not seem to be affected by the presence of heparin or oral
anticoagulants.54<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C54>The
specificity of the ECT-determined
lepirudin concentration is not influenced by treatment with oral
anticoagulants. ECT is a rapid, sensitive clotting assay suitable
*for*precise measurement of plasma concentrations of
lepirudin in non-prothrombin-deficient states without interference from
heparin or aprotinin or from treatment with oral
anticoagulants.54<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C54>
Published
clinical data regarding the use of this monitoring tool come mainly from
case reports. Ecarin clotting time values showed good correlation with
plasma concentrations of lepirudin. In these reports, an ECT of 350–400 s
corresponds to lepirudin concentrations of 3.5– 4 µg
ml–1.42<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C42>
The Heparin-Associated Thrombocytopenia Trials (HAT-1 and
HAT-2)24<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C24>
25 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C25> are
prospective clinical trials of lepirudin. The clinical outcomes of patients
were compared with those of a historical control group. A meta-analysis of
these trial results29<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C29>represents
the largest
population of patients with *HIT* and thromboembolic complications treated
with lepirudin. Overall, 198 patients (82 in HAT-1, 116 in HAT-2) were
treated with lepirudin and 182 historical control patients were given other
treatments. All except five (one in HAT-1, four in HAT-2 group) prospective
patients and all historical control patients were diagnosed with *HIT*
using the
heparin-induced platelet activation assay or equivalent assays
*for*testing. In total, 113 (54 in HAT-1, 59 in HAT-2) prospective
patients (lepirudin) and 91 historical control patients presented with
thromboembolic complications at baseline (day of positive test result) and
qualified *for* direct comparison of clinical endpoints.
In the meta-analysis, the pooled lepirudin patients of the HAT-1 and HAT-2
studies who presented with thromboembolic complications at baseline were
compared with the respective historical control patients. Seven and 35 days
after the start of treatment, the cumulative risks of death were 4.4 and
8.9% respectively in the lepirudin group, compared with 1.4 and 17.6% in the
historical control group. The cumulative risks of limb amputation were 2.7and
6.5% in the lepirudin group compared with 2.6 and 10.4% in the historical
control group. Most importantly, the cumulative risks of new thromboembolic
complications were 6.3 and 10.1% in the lepirudin group and 22.2 and
27.2%in the historical control
group. The differences in the cumulative risk of death, limb amputation or
new thromboembolic complications between the groups were statistically
significant in favour of lepirudin in the analysis of time to event (*P*=
0.004).
*Bivalirudin* (Angiomax(r)) is a direct thrombin inhibitor and an analogue of
the peptide fragment hirugen, a compound derived from hirudin. Unlike
lepirudin, the binding of bivalirudin to thrombin is reversible. Bivalirudin
binds specifically to the catalytic site and substrate-binding site of
thrombin. Bivalirudin has been approved by the US Food and Drug
Administration (FDA) *for* use in patients undergoing coronary angioplasty
with unstable angina who are also on aspirin therapy.
*Argatroban* (Argatroban(r), Novastan(r)) is a direct competitive synthetic
inhibitor of thrombin derived from L-arginine, with a molecular weight of
526. It binds reversibly to the thrombin catalytic site and thus inhibits
reactions that are catalysed or induced by the presence of soluble and
clot-bound thrombin. Actions inhibited by the presence of argatroban include
fibrin *for*mation and activation of coagulation factors V, VIII and XIII
and the natural anticoagulant protein
C.34<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C34>
51 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C51>
61<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C61>
It
is 100% bioavailable when given i.v. and is metabolized in the liver by
cytochrome P450 enzymes. Unchanged drug is excreted in the urine (16%) and
faeces (14%). The primary metabolite exerts an anticoagulant effect that is
three to five times less potent than that of the parent drug. It is
eliminated as its metabolite in the faeces (65%), presumably through biliary
secretion, and in the urine (22%). Argatroban is contraindicated in
patients with
active bleeding or known hypersensitivity to the agent. Bleeding is the
major adverse effect of argatroban, occurring in 2.3–14.4% of patients in
clinical trials. The effective dose is titrated against the aPTT and
activated clotting time (ACT). The drug has a predictable pharmacokinetic
and pharmacodynamic profile, and there is dose-dependent response in aPTT
and ACT.
Argatroban is given as an initial bolus of 2 µg kg–1 min–1 in adult patients
without hepatic impairment. The infusion rate is titrated according to the
desired level of anticoagulation. An aPTT ratio of 1.5–3.0 is usually
achieved within 4 h of i.v. administration.
A study with argatroban enrolled 304 patients into two arms—160 patients in
the *HIT* arm and 144 in the *HIT*T arm (Table
7<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063TB7>).
They were compared with 193 historical control subjects with *HIT* (*n*=147)
or *HIT*T (*n*=46).44<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C44>Outcomes
of these patients were compared with
those of the historical controls *for* a period of 37 days after
administration of argatroban in the treatment group and after diagnosis of *
HIT* or *HIT*T in the control group. The primary efficacy end-point was a
composite of all-cause death, all-cause amputation and new thrombosis within
37 days of baseline. The secondary efficacy end-point included the
individual components of the composite end-point together with death caused
by thrombosis, any new thrombosis, achievement of adequate anticoagulation, and
resolution of thrombocytopenia. Argatroban was initiated at 2 µg kg–1
min–1and titrated to
maintain aPTT at 1.5–3 times baseline *for* 14 days. Treatment continued *
for* an average of 5.3 days in the *HIT* group and 5.9 days in the *HIT*T
group. In patients with *HIT*, argatroban therapy significantly reduced new
thrombosis when compared with control subjects (8.1 *vs* 22.4%, *P*<0.001).
However, the reduction in new thromboses in patients with *HIT*T on
argatroban therapy was more modest when compared with the reduction in the
controls (19.4 *vs* 34.8%, *P*=0.044). There was no decrease in death or
amputation caused by all causes in the *HIT* and *HIT*T groups, but a
significant reduction was seen in death caused by thrombosis in both groups
(*P*=0.005 and *P*<0.001 respectively). Argatroban was associated with more
rapid resolution of thrombocytopenia and no increase in bleeding. Argatroban
has also been shown to be more effective than heparin *for* coronary
reperfusion after the use of recombinant tissue plasminogen activator
(r-tPA) in acute myocardial
infarction.36<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C36>
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*Table 7* Results of argatroban study: categorical efficacy
analysis.44Values are
*n* (%). aAll-cause death, all-cause amputation or new thrombosis within
37-day study period; bseverity ranking: all-cause death > all-cause
amputation > new thrombosis; patients with multiple outcomes counted
once; cpatients
counted only once if multiple events occurred. (Adapted with permission from
Lewis *et al*.)44
The use of warfarin with argatroban results in prolongation of the INR
beyond that produced by warfarin alone. *For* doses up to 2 µg kg–1 min–1,
the equivalent INR on warfarin alone (INRW) can be calculated from the INR *
for* cotherapy of warfarin and argatroban (INRWA) according to a published
graph.48 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C48>The
error associated with this prediction is
±0.4 units. *For* argatroban doses >2 µg kg–1 min–1, the relationship is
less predictable and the error of prediction is ±1 units. The equivalent INR
on warfarin alone (INRW) cannot be predicted reliably from the INRWA at
doses greater than 2 µg kg–1
min–1.48<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C48>
*Other alternatives in HIT*
There are no convincing data available *for* the use of the following
alternatives.
However, they may have a role as an adjunct with other
anticoagulants:23<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C23>
67 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C67>
(i) intravenous immunoglobulins (IgG class);
(ii) platelet transfusion—can increase new thromboembolic complications and
is not indicated currently even as an adjunct in the treatment of *HIT*;
(iii) plasma exchange—its effectiveness is in doubt;
(iv) fresh frozen plasma—some use in *HIT* complicated by warfarin therapy;
(v) glycoprotein IIb/IIIa inhibitor.
*Post-heparin thrombosis*
Studies have shown that *HIT* antibodies are capable of activating platelets
in a non-heparin-dependent manner, as a result of the generation of
'superactive' *HIT*
antibody.1<http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C1>Using
serum
of patients with *HIT*T, peripheral blood monocytes and monoclonal
antibodies specific *for* H–PF4, researchers have shown that monoclonal
antibodies and antibodies from patients with *HIT*T induce monocyte
activation with secretion of interleukin 8 and cell-surface procoagulant
activity. The time-dependence of these changes *in vitro* (>6 h) far exceeds
the short incubation period (<1 h) required *for* platelet activation by
H–PF4 antibodies. Hence, it is suggested that these changes in the monocyte
could amount to the pathogenesis of thrombi after the discontinuation of
heparin.5 <http://bja.oxfordjournals.org/cgi/content/full/90/5/676#AEG063C5>
*Summary*
It is important to have a high index of clinical suspicion in a patient with
a falling platelet count who is receiving heparin. It is imperative to
discontinue all sources of heparin even be*for*e the laboratory confirmation
of *HIT*. Platelet transfusion is contraindicated as this can exacerbate the
serious thrombotic complications. Circulating antibodies bind to the
transfused platelets and release platelet microparticles, leading to a
thrombotic
state. Treatment is intended to reduce the thromboembolic complications.
There are several pharmaceutical agents available *for* the treatment of *
HIT*. Be*for*e starting any of these agents, the clinician should decide
which of them is safe and effective *for* the individual patient. Lepirudin
is an irreversible, direct thrombin inhibitor that has shown effectiveness
in treating patients with *HIT* type II. It does not cross-react with
heparin and can be readily monitored with the aPTT and ECT.
Disadvantages include
a prolonged half-life, prolongation of the prothrombin time, possible
antibody *for*mation, and the requirement *for* dose adjustments in patients
with renal impairment. Argatroban is the newest agent used *for* *HIT* type
II. It binds reversibly to thrombin and is monitored with the aPTT. Patients
who require anticoagulation and have renal impairment may benefit from the use
of argatroban because of its hepatic metabolism. A disadvantage of this
agent is prolongation of the prothrombin time (necessitating additional
monitoring in patients who are also receiving warfarin), and dose adjustment
in patients with hepatic impairment. Danaparoid, *prostacyclin* analogues
and desirudin, although previously used in *HIT*, are not licensed *for* the
treatment of *HIT* or *HIT*T.
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2007/10/16, Michael Firstenberg <msfirst at gmail.com>:
>
> You can get heparin free swans.
>
> Michael Firstenberg <msfirst at gmail.com>
>
> -----Original Message-----
> From: "V. Aldrete, M.D." <valdretemd at shaw.ca>
> To: OpenHeart-L at lists.hsforum.com
> Sent: 10/15/2007 9:45 PM
> Subject: Re: [HSF] Heparin Induced Thrombocytopenia and CABG
>
> Indications for surgery aside I just wanted to let you know that the
> Swan Ganz catheters have bonded heparin. It will leach after insertion.
>
> I had the horrible experience of having a patient with true allergy
> to heparin (bronchospasm) and all, for which I used Ancrod for CPB
> anticoagulation as described by:
>
> Zulys VJ. Teasdale SJ. Michel ER. Skala RA. Keating SE. Viger
> JR. Glynn MF.
> Department of Anaesthesia, Toronto General Hospital, Ontario, Canada.
> Ancrod (Arvin) as an alternative to heparin anticoagulation for
> cardiopulmonary bypass.
> Anesthesiology. 71(6):870-7, 1989 Dec.
>
> Good luck,
>
> Victor
>
>
> On Oct 15, 2007, at 5:52 PM, Cysmd613 at aol.com wrote:
>
> > Need advice on a case which I cancelled today. 64 yo morbidly obese
> > diabetic woman with chronic renal insufficiency admitted 11 days
> > ago with angina.
> > Did not have an MI. Stress test positive. Cath showed 50-60%
> > distal left
> > main, 60% ostial circ, 70% RCA with good LV. History of
> > thrombocytopenia with
> > negative bone marrow biopsy in past. Platelet count on admission
> > 97,000 which
> > slowly dropped to 67,000. She had been on IV heparin. Yesterday
> > morning
> > when I made rounds she was still on heparin. Hematologist ordered
> > platelet
> > transfusions on call to OR. This morning, I got a call from the
> > anesthesiologist who was lining the patient in the OR, saying that
> > the patient is on
> > Refludan, and what was my plan for anticoagulation on bypass. You
> > can imagine my
> > surprise!! Yesterday evening, the cardiologist, without calling
> > me first,
> > stopped the patient's heparin and switched to Refludan because of the
> > thrombocytopenia. No heparin antibody had been done yet. Just
> > from the neck sticks for
> > the IJ central line and swan-ganz, the patient was bleeding
> > significantly.
> > So, I cancelled the case. Blood was drawn and the heparin antibody is
> > POSITIVE.
> >
> > Now, how to proceed? I would not do CABG using Refludan as it is not
> > reversible. Should I use heparin, transfuse platelets as needed
> > and hope for no
> > intravascular thrombosis?
> >
> > Thank you for your input.
> >
> > Carmi Stadlan
> >
> >
> >
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--
Claudia Teles
Hemostasis Section - INCARDIO
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